Stem cell growth directs region-specific cell fate decisions during intestinal nutrient adaptation

Abstract

ABSTRACTThe adult intestine is a regionalized organ, whose size and cellular composition is adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell type composition remains unclear. Here we show that nutrient adaptation involves region-specific control of intestinal cell size, number and differentiation. We uncovered that activation of mTOR complex 1 increases ISC size in a region-specific manner. This promotes Delta expression to direct cell fate towards the absorptive enteroblast lineage, while inhibiting secretory enteroendocrine cell differentiation. The observed coupling between nutrient sensing and cell fate enabled mitigation of aging-induced ISC misdifferentiation through intermittent fasting. In conclusion, ISC size acts as an early fate determinant allowing regional control of intestinal cell differentiation in response to nutrition with relevance to maintenance of tissue integrity during aging.HighlightsmTORC1 signaling regulates ISC size in a region-specific mannermTORC1 signaling is activated in the S and G2 phase of the ISC cell cycleISC size directs differentiation towards absorptive vs. secretory lineageIntermittent fasting mitigates aging induced deregulation of ISC differentiationGRAPHICAL ABSTRACT